Design of a catalytic scavenger for Organo-phosphorous compound – CAT-SCAV

Find an efficient solution for neutralization of organophosphorus nerve agents in vivo, in order to protect or cure people is a concern of public health. Such organophosphorus-based compounds are used as chemical weapons or pest control agents. The need of a biocompatible mean for their neutralization takes into account both their potential use within wartime or terrorist actions, and acute or chronic intoxications by insecticides. This project aims at unifying the efforts of two research groups in order to develop catalytic biocompatible scavengers. Depending on their biocompatibility, these agents will be used either in vivo as prophylactic or curative means, or will be incorporated into creams or foams for skin, mucosae and wound decontamination.

Organophosphorus compounds (OP) are among the most toxic compounds synthesized due to their irreversible inhibition of acetylcholinesterase. A catalytic bioscavenger present in the bloodstream can neutralize the neurotoxics before they reach their biological target at the synapse or neuromuscular junction. Injected bioscavenger will be an important pretreatment tool in case of severe intoxication risk, for example for military personnel going in a conflict area where neurotoxics are potentially used, or for civilian emergency personnel going to the site of a chemical terrorist attack. For intoxicated people, a massive dose of bioscavenger can be injected to rapidly eliminate the toxic from the body, thus leading to a faster recovery.

Human butyrylcholinesterase (BChE) is an enzyme for which modifying its catalytic activity has been an ongoing subject of interest. Considerable interest has been shown in BChE because it hydrolyses a wide range of toxic esters, including heroin and cocaine, and because it scavenges organophosphorus pesticides and nerve agents. Redesign of its active site has improved its cocaine hydrolase activity 2000-fold, turning it into a very efficient cocaine-detoxifying tool. This BChE variant is effective at detoxifying cocain in vivo, and we propose a similar approach for neurotoxics in the present project.

IRBA teams and others have explored the development of catalytic scavenger for OP molecules during the last decades. Nowadays, the BChE G117H variant and human paraoxonase (PON1) have a catalytic activity against OP, but this activity is not efficient enough for practical use. In 2008, Baker succeeded in modifying the activity of a protein by adding an appropriate chemical function with the help of molecular modeling and bioinformatics tools. The aim here is to use these tools to modify BChE in order to introduce a performant OP hydrolase activity. Since 2002, our institute develops a softwaresoftware called SuMo whichSuMo, which will be included in the general methodology published by Baker. The use of this software will unlock the limitation of the choice of scaffold protein. Each protein constructed and validated in silico will be synthesized by the IRBA team and tested for hydrolase activity on nerve agents and pesticide. The lead hit will constitute the active ingredient of new medical countermeasure against the intoxication by organophosphorus neurotoxics.